Leptin resistance in mice is determined by gender and duration of exposure to high-fat diet.

Mice fed a high-fat diet are reported to be resistant to peripheral injections of leptin. We previously failed to induce leptin resistance in female mice fed a high-fat diet for 15 weeks. Therefore, we measured the responsiveness to peripheral infusions (10 microg/day) of leptin, and the responsiveness to third ventricle injections of leptin (1 microg) in male and female NIH Swiss mice fed low-fat (10% kcal) or high-fat (45% kcal) diets. Male and female 15-week-old mice that had been fed low- or high-fat diet from 10 days of age lost fat during a 13-day intraperitoneal infusion of leptin and lost weight in response to a single central injection of leptin. Fifteen-week-old male mice fed a high-fat diet for 5 weeks did not lose body fat during a peripheral infusion of leptin and did not lose weight in response to a central injection of leptin. Female mice fed high-fat diet for 5 weeks remained leptin-responsive. Weight loss was achieved without a significant voluntary decrease in food intake, suggesting that both peripherally and centrally administered leptin increases energy expenditure. These results demonstrate that the development of leptin resistance in NIH Swiss mice fed a high-fat diet is dependent upon the gender of the mice and either the duration of exposure to high-fat diet or the age at which the mice are first exposed to the diet.